PT949905E - DELAYED EFFECT INJECTABLE GEL COMPOSITION AND PROCESS FOR THEIR PREPARATION - Google Patents

Abstract

Methods and compositions for systemically or locally administering by implantation a beneficial agent to a subject are described, and include, for example, compositions having burst indices of 8 or less for systemic applications and systems releasing 10% or less of the total dose of beneficial agent in the first 24 hours after implantation for local applications. The compositions include a biocompatible polymer, a biocompatible solvent having low water miscibility that forms a viscous gel with the polymer and limits water uptake by the implant, and a beneficial agent.

Description

COMPOSITION OF RETARDED EFFECT INJECTABLE GEL AND PROCESS FOR THEIR PREPARATION

The present invention relates to a delayed effect gel composition which may be injected at a desired location and which may provide sustained release of a beneficial agent. The present invention also relates to a process for the preparation of the composition.

Description of Related Art

Biodegradable polymers have been used for many years in medical applications. Illustrative devices of biodegradable polymer compounds include sutures, surgical tweezers, staples, implants, and drug delivery systems. Most of these biodegradable polymers have been based on glycosides, lactides, caprolactone and their copolymers.

Biodegradable polymers can be thermoplastic materials, which means they can be heated and molded in various forms, such as fibers, tweezers, staples, pins, films, etc. Alternatively they may be thermoforming materials formed by SGCR-0418 cross-linking reactions which lead to high molecular weight materials which do not melt or form liquid-flowable liquids at high temperature.

Although thermoplastic and thermomoldable biodegradable polymers have many useful biomedical applications, there are several important limitations to their use on the bodies of various animals, including humans, animals, birds, fish and reptiles. Because these polymers are solid, all instances involving their use have required the initial formation of polymer structures outside the body, followed by insertion of the solid structure into the body. For example, sutures, tweezers and staples, all are formed from biodegradable thermoplastic polymers prior to use. When inserted into the body they retain their original shape. While this feature is essential for some uses, it represents a disadvantage in cases where the material is intended to flow to fill empty spaces or cavities where it is most needed.

Ingredient delivery systems using biodegradable thermoplastic or thermomoldable polymers also have to be formed out of the body. In these circumstances, the drug is incorporated into the polymer and the blend is configured in a certain form, such as a cylinder, a disk or a fiber for implantation. With such solid implants the drug delivery system has to be inserted into the body through an incision. Sometimes these incisions are larger than intended by the medical profession and occasionally lead to reluctance 2

SGCR-0418 of patients in accepting such an implant or drug delivery system. Nonetheless, both biodegradable and non-biodegradable drug delivery systems have been widely used successfully.

A reservoir device having a rate control membrane and a zero-order release of an agent which is particularly designed for intraoral implantation is described in U.S. Patent No. 5,085,866. The device is prepared from a core which is sprayed with a solution containing a polymer and a solvent which is composed of a first fast evaporating solvent, a low boiling point and a second high boiling point evaporating solvent.

Other illustrative osmotic delivery systems include those disclosed in U.S. Pat. 3,797,490, 3,987,790, 4,008,719, 4,865,845, 5,057,318, 5,059,423, 5,112,614, 5,137,727, 5,151,093, 5,234,692, 5,234,693, 5,279,608 and 5,336. 057. Pulsatile delivery devices are also known which deliver a beneficial agent in a pulsatile manner, as disclosed in U.S. Pat. 5,209,746, 5,308,348 and 5,456,679.

One way of avoiding the incision necessary to implant drug delivery systems is to inject them as small particles, microspheres or microcapsules. For example, U.S. Patent No. 5,019,400 describes the preparation of controlled release microspheres by means of SGCR-0418 a release process at a very low temperature. These materials may or may not contain a drug that can be released into the body. Although these materials can be injected into the body with a syringe, they do not always meet the requirements of a biodegradable implant. Because they are particulate by nature, they do not form a continuous film or solid implant with the structural integrity required for certain prostheses. When inserted into certain body cavities such as the mouth, periodontal pocket, eyes, or vagina, where there is a considerable flow of fluid, these small particles, microspheres or microcapsules, are poorly retained because of their small size and discontinuous nature. In addition, the particles tend to aggregate and so it is difficult to predict their behavior. In addition, microspheres or microcapsules prepared from these polymers and containing drugs for release into the body are sometimes difficult to produce on a large scale and their storage and injection characteristics present problems. In addition, one of the major limitations of the microcapsule or small particle system is its lack of reversibility without extensive surgical intervention. That is, in the case of complications after they have been injected, it is considerably more difficult to remove them from the body than with solid implants. Yet another limitation of microparticles or microcapsulation lies in the difficulty of encapsulating proteins and DNA-based drugs without the degradation caused by solvents and extreme temperatures. 4 SGCR-0418 The art has developed various drug delivery systems in response to the challenges mentioned above. For example, U.S. Patent No. 4,938,763 and U.S. Patent No. 5,278,201 relate to a biodegradable polymer for in situ, biodegradable solid animal implants suitable for use with syringes. In one embodiment, a thermoplastic system is used in which a non-reactive polymer is dissolved in a biocompatible solvent to form a liquid which is placed into the animal in which the solvent dissipates to produce the solid implant. Alternatively, a thermomoldable system is used in cases where effective amounts of a liquid acrylic ester, a biodegradable prepolymer and a curing agent are formed and the liquid mixture is placed into the interior of the animal in which the prepolymer matures to form the implant solid. The systems have been reported to provide a biodegradable solid delivery system, capable of being delivered by injection, by adding an effective level of a biologically active agent to the liquid, prior to injection into the animal. U.S. Patent No. 5,242,910 describes a sustained release composition for treatment of periodontal diseases. The composition comprises lactide and glycolide copolymers, triacetin (as a solvent / plasticizer) and an agent for relief of diseases of the oral cavity. The composition may take the form of a gel and may be inserted into a periodontal cavity by means of a syringe using both a needle and a catheter. As optional additional SGCR-0418 components, the composition may contain surfactants, flavoring agents, viscosity control agents, binders, antioxidants, other polymers, gums, waxes / oils, and coloring agents. An illustrative viscosity control agent mentioned in one of the examples is polyethylene glycol 400.

With delayed solvent-based compositions consisting of a polymer dissolved in a solvent, there is a problem that the composition slowly solidifies after injection as the solvent is released from the reservoir. Since these compositions have to be non-viscous to be injected, a large percentage of drug is released as the system is formed by diffusion of the solvent. This effect is referred to as an "explosion" effect. In this regard, it is typical for the solvent-based compositions to have an explosion of the drug in which 30-75% of the drug contained in the composition is released within one day after the initial injection

SUMMARY OF THE INVENTION The present invention is a significant advance in the art and in one aspect provides a delayed-effect injectable gel composition comprising: A) a biocompatible polymer; B) a solvent which dissolves the polymer and forms a viscous gel; 6 SGCR-0418

C) a beneficial agent; and D) an emulsifying agent in the form of a droplet phase dispersed in the viscous gel.

In another aspect, the present invention provides a process for the preparation of a delayed-effect injectable gel composition comprising: A) mixing a biocompatible polymer and a solvent by virtue of which the solvent dissolves the polymer and forms a gel viscous; B) dispersing or dissolving a beneficial agent in the viscous gel to form a beneficial agent containing gel; and C) mixing an emulsifying agent with the gel-containing beneficial agent, wherein said emulsifying agent forms a droplet phase dispersed in the beneficial agent containing gel so as to provide the injectable gel composition having a delayed effect.

In another aspect, the present invention provides a process for the preparation of a delayed-effect injectable gel composition comprising: A) mixing a biocompatible polymer and a solvent by virtue of which the solvent dissolves the polymer and forms a gel viscous; B) dispersing or dissolving a beneficial agent in an emulsifying agent to form a beneficial agent containing emulsifying agent; and C) mixing the beneficial agent containing the emulsifying agent with the viscous gel, said beneficial agent containing emulsifying agent forming a droplet phase dispersed in the viscous gel to provide the injectable gel composition having a delayed effect.

Yet another aspect the invention provides a delayed-effect injectable gel composition comprising: A) a biocompatible polymer; B) a solvent which dissolves the polymer and forms a viscous gel; C) an emulsifying agent in the form of a droplet phase dispersed in the viscous gel.

In a further aspect, the invention provides a kit adapted to provide a delayed-effect injectable composition comprising, as components of the kit: (a) a biocompatible polymer and a solvent that dissolves the polymer and forms a viscous gel; (b) emulsifying agent; and (c) beneficial agent. 8

SGCR-0418

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of the present invention will be more readily understood by reading the following detailed description in conjunction with the drawings in which: Figure 1 is a graph illustrating the dispensing force required to dispense the viscous gel compositions emulsified and non-emulsified through a 20 gauge needle in 2cc / minute psig; Figure 2 is a graph illustrating the lysozyme release profiles of three different compositions in days; and Figure 3 is a graph illustrating the viscosity profiles at different shear rates only of water and an aqueous mixture of ethanol and the viscous gel without emulsifying agent.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

As explained above, one aspect of the present invention relates to a delayed-effect injectable gel composition comprising: A) a biocompatible polymer; B) a solvent that dissolves the biocompatible polymer and forms a viscous gel; C) a beneficial agent; and D) an emulsifying agent in the form of a droplet phase dispersed in the viscous gel. The polymer, solvent and emulsifying agents of the invention must be biocompatible, i.e., they should not cause irritation or necrosis in the environment of use. The environment of use is a fluid environment and may comprise a subcutaneous or intramuscular zone or a cavity of the body of a human or animal.

Polymers which may be useful for the invention may be biodegradable and may include, but are not limited to, polylactides, polyglycols, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyquotals, polycarbonates, polyorthocarbonates, polyphosphazenes, succinates, poly (malic acid), poly (amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan and copolymers, terpolymers and mixtures thereof. The polymer may be a polylactide, i.e., a lactic acid based polymer which may be lactic acid based only or may be a lactic acid and glycolic acid copolymer which may include small amounts of other comonomers which are not substantially affect the advantageous results which can be achieved in accordance with the present invention. As used herein, the term "lactic acid" includes the isomers L-lactic acid, D-lacido acid, DL-10 acid SGCR-0418

lactic acid and lactosides while the term "glycolic acid" includes glycolides. The polymer may have a lactic acid / glycolic acid monomer ratio of from about 100: 0 to about 15:85, preferably from about 60:40 to about 75:25, and a particularly useful copolymer has a ratio of monomer of lactic acid / glycolic acid of about 50:50. The lactic acid-based polymer has an average molecular weight of from about 1,000 to about 120,000, preferably from about 10,000 to about 30,000, as determined by gas phase chromatography. As indicated in U.S. Pat. No. No. 5,242,910, the polymer may be prepared in accordance with the teachings of U.S. Pat. No. 4,443,340. Alternatively the lactic acid based polymer may be prepared directly from lactic acid or a mixture of lactic acid and glycolic acid (with or without a comonomer) according to the techniques set forth in U.S. Patent No. 5,310,865. The contents of all these patents are hereby incorporated by reference. Suitable lactic acid-based polymers are available commercially. For example, Boehringer Ingelheim (Petersburg, VA) has available 50:50 lactic acid / glycolic acid copolymers having molecular weights of 10,000, 30,000 and 100,000. The biocompatible polymer is present in the composition in an amount ranging from about 5 to about 80% by weight, preferably from about 20 to about 50% by weight and often 35 to 45% by weight of the viscous gel in that the viscous gel contains the combined amounts of the biocompatible polymer and the solvent. Once placed in the environment of use, the solvent will slowly release from the reservoir and the polymer will slowly degrade by hydrolysis. The solvent must be biocompatible and is chosen so as to dissolve the polymer to form a viscous gel which can keep particles of the beneficial agent dissolved or dispersed and isolated from the environment of use prior to release. Exemplary solvents which may be used in the present invention include, but are not limited to, triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone, formal glycerol, methyl acetate, benzyl benzoate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, caprolactan, decylmethylsulfoxide, oleic acid, and 1-dodecylazacycloheptan-2-one and mixtures thereof. Preferred solvents are triacetin and N-methyl-2-pyrrolidone. Triacetin provides a high level of polymer dissolution which leads to higher gel viscosities, which requires the user to have greater strength to dispense the viscous gel when compared to other solvents. These characteristics allow the beneficial agent to be maintained without exhibiting an explosion effect, but make it difficult to dispense the gel through a needle. As shown in Figure 1, for example, a gel prepared from a 50:50 lactic acid / glycolic acid 40 wt% polymer and 60 wt% triacetin required about 40 psig to dispense the gel through a standard gauge of 20 to 2 cc / minute while a gel prepared from the same amount of polymer with 60% by weight of N-methyl-2-pyrrolidone required only about 8 psig of SGCR-0418. Figure 1 also shows that when the emulsifying agent (in this case 33% by weight of a 10% ethanol solution) is added to the viscous gel according to the invention, the force required to dissolve it is only about 2% psig. The fine-cut characteristics of the delayed-effect gel compositions of the present invention allow them to be readily injected into an animal, including humans, using standard gauge needles without requiring undue dispensing pressure.

Typically the solvent is present in an amount ranging from about 95 to about 20% by weight and is preferably present in an amount ranging from about 80 to about 50% by weight and often from 65 to 55% by weight of the viscous gel, i.e. the combined amounts of the polymer and the solvent. Typically the viscous gel formed by mixing the polymer and the solvent exhibits a viscosity ranging from about 1,000 to about 200,000 poise, preferably from about 5 to about 50,000 poise, measured at a shear rate of 1.0 seconds -1 at 25 ° C using a Haake Viscometer about 1-2 days after mixing is complete. The mixing of the polymer with the solvent can be achieved with conventional low shear equipment such as a Ross twin planetary mixer for about 1 to 2 hours. The beneficial agent may be any physiologically or pharmacologically active substance or substances, or optionally in combination with pharmaceutically acceptable carriers and additional ingredients such as antioxidants, stabilizing agents, permeability enhancers, etc. which do not substantially and adversely affect the advantageous results obtainable by the present invention. The beneficial agent may be any of the agents known to be delivered to the body of a human or animal and which are preferably more soluble in water than in the polymer dissolution solvent. These agents include drug agents, medicaments, vitamins, nutrients and the like. The types of agents indicated in this disclosure include nutrients, vitamins, dietary supplements, sex sterilizers, fertility inhibitors and fertility promoters.

Drugs that may be delivered with the present invention include drugs that act on peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscles, the cardiovascular system, smooth muscles, blood circulation system, synoptic points, neuro-effective junctional sites, endocrine and hormonal systems, the immune system, the reproductive system, the skeletal system, autacoid systems, the feeding and excretory systems, the histamine system and the central nervous system. Suitable agents may be selected, for example, from among proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, anti-inflammatory corticosteroids, ophthalmic drugs and analogous synthetic products of these species. 14 SGCR-0418 \ and

Examples of drugs which may be provided through the composition of the present invention include, but are not limited to, prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, mecamylamine hydrochloride, procainamide hydrochloride, amphetamine sulfate, methamphetamine hydrochloride, amphetamine hydrochloride , isoproterenol sulfate, phenmetrazine hydrochloride, bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropamide iodide, tridiexethylchloride, phenformin hydrochloride, methylphenidate hydrochloride, theophylline hydrochloride, hydrochloride of cephalexin, diphenhydrin, meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiettilperzine maleate, anisindona, erythrtyl dimethadione tetranitrate, digoxin, isoflurofate, acetazolamide, bendroflumethiazide, chlorpromazine, tolazamide, chloromadinone acetate, fenaglicodol, allopurinol, aluminum aspirin , methotrex acetyl sulfisoxazole, erythromycin, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, dexamethasone and derivatives thereof such as betamethasone, triamcinolone, methyltestoterone, 17-S-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone, Norethindrone, norethindrone, norethisterone, norethionone, progesterone, norgesterone, norethinodrel, aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbidine dinitrate, propranolol, timolol, atenolol , alprenolol, cimetidine, clonidine, imipramine, lcvodopa, chloropromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinone, mandol, quanbenz, hydrochlorothiazide, ranitidine, fluobiprofen, fenufen, fluprofen, tolmetin, allofenine c, mefenamic, flufenamic, difuinal, nimodipine, nitrendipine, nicardipine, felodipine, lidoflazine, tiapamil, galopamil, amlodipine, myloflazine, lisinolpril, enalapril, enalaprilat, captopril, ramipril, famotidine, nizatidine, sucralfate, ethintidine, tetratolol, minoxidil , chlorodiazepide, diazepam, amitriptyline, and imipramine. Other examples are proteins and peptides which include, but are not limited to, bone morphogenic proteins, insulin, colchicine, glucagon, thyroid stimulating hormone, pituitary and parathyroid hormones, calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone, stimulating hormone of follicles, chorionic gonadotrophin, gonadotropin releasing hormone, bovine somatotropin, porcine somatotropin, oxytocin, vasopressin, GRF, somatostatin, lipressin, pancreozyme, luteinizing hormone, LHRH, agonists and φ antagonists of LHRH, leuprolide, interferons, interleukins, hormones of growth hormone such as human growth hormone, bovine growth hormone and porcine growth hormone, fertility inhibitors such as prostaglandins, fertility promoters, growth factors, coagulation factors, human pancreatic hormone releasing factor, analogues and derivatives of these compounds, and salts of these compounds pharmaceutically acceptable salts, or analogs or derivatives thereof. 16 SGCR-0418

For those not mentioned in the previous paragraph, the beneficial agents described in the aforementioned U.S. Patent No. 5,242,910 may also be used. A particular advantage of the present invention is that materials such as proteins, as exemplified by the enzyme lysozyme and cDNA and DNA incorporated in both the viral and nonviral vectors, which are difficult to microcapsulate or process in microspheres, may be incorporated into the compositions of the present invention invention without the level of degradation experienced with other techniques.

Preferably, the beneficial agent is incorporated into the viscous gel formed from the polymer and the solvent in particulate form, typically having a mean particle size ranging from about 0.1 to about 100 microns, preferably from 1 to about 25 microns and often 2 to 10 microns. For example, particles with an average particle size of about 5 microns were generated by dry spray or ice-cold spray in an aqueous mixture containing 50% sucrose and 50% pinto lysozyme (on a dry weight basis). Such particles have been used in some of the examples shown in the figures.

To form a suspension of particles of the beneficial agent in the viscous gel formed from the polymer and the solvent any conventional low shear device such as a Ross double planetary blender can be used at ambient conditions. In this way, an effective distribution of the beneficial agent without degradation of the beneficial agent can actually be achieved. 17 SGCR-0418

Typically the beneficial agent is dissolved or dispersed in the composition in an amount ranging from about 1 to about 50% by weight, preferably in an amount ranging from 5 to 25% and often from 10 to 20% by weight of the combined amounts of the polymer, the solvent and the beneficial agent. Depending on the amount of beneficial agent present in the composition, different release profiles may be obtained. More specifically, for a given polymer and solvent, by adjusting the amounts of these components and the amount of the beneficial agent, a release profile can be obtained which depends more on the degradation of the polymer than on the diffusion of the beneficial agent from the composition , or vice versa. In this regard, lower loading rates of the beneficial agent generally provide a release profile reflecting the degradation of the polymer in which the release rate increases with time. At higher loading rates, a release profile is generally obtained by diffusion of the beneficial agent in which the rate of release decreases with time. At intermediate loading rates, combined release profiles are obtained so that, if desired, a substantially constant release rate can be achieved. While a specific release rate depends on particular circumstances, such as the beneficial agent to be administered, release rates in the range of 1 to about 10 micrograms / day may be obtained for periods ranging from about 7 to about 90 days . In addition, the dose of bcncphic agent may be adjusted by adjusting the amount of injectable delayed injected gel. As will be pointed out 18 SGCR-0418

of the following results, an explosion effect can be avoided and administered on the order of 1% by weight of the beneficial agent in the composition during the first day. Figure 2 illustrates the release rates obtained from the compositions described with respect to Figure 1. The gel prepared from a polymer of 40 wt% of 50:50 lactic acid / glycolic acid and 60 wt% of triacetin is thick and therefore difficult to inject but reveals small outbreaks (less than 2% of the beneficial agent is distributed in the first eight days). The gel prepared from a polymer of 40 wt.% Of lactic acid / glycolic acid and 60% of N-methyl-2-pyrrolidone is thin and injectable but shows a large explosion (greater than 70% of the beneficial agent is distributed in the first eight days). The gel prepared from a polymer of 27% by weight of 50:50 lactic acid / glycolic acid, 40% by weight of triacetin and 33% by weight of 10% ethanol, 90% isotonic saline solution is thin and injectable and shows weak burst (less than 10% of the beneficial agent is distributed in the first eight days). In each case lysozyme is the beneficial agent and comprises 20% by weight of the combined beneficial agent, polymer and solvent formulation. The emulsifying agent is an important aspect of the present invention. When the emulsifying agent is mixed with the viscous gel formed from the polymer and the solvent using conventional, static or mechanical mixing devices, such as an orifice mixer, the emulsifying agent forms a separate phase composed of SGCR-0418 dispersed droplets of which typically have an average diameter of less than about 100 microns. The continuous phase is formed of the polymer and the solvent. The particles of the beneficial agent may be dissolved or dispersed, both in the continuous phase and in the droplet phase. In the resulting thixotropic composition, the droplets of emulsifying agent elongate in the cutting direction and substantially decrease the viscosity of the viscous gel formed from the polymer and the solvent. For example, with a viscous gel having a viscosity ranging from 5,000 to about 50,000 poise, measured at 1.0 sec-1 at 25 ° C, a reduction in viscosity can be obtained to less than 100 poise when emulsified with a 10% ethanol / water solution at 25 ° C as determined by the Haake rheometer. Because the dispersion and dissolution of the beneficial agent particles in the emulsifying agent proceeds more rapidly than the dissolution or dispersion of the beneficial agent in the viscous polymer, the beneficial agent can be mixed with the emulsifying agent just before use. This allows the beneficial agent to be maintained in a dry state prior to use, which may be advantageous in cases where there is a long term stability of the beneficial agent in the viscous gel. In addition, once the beneficial agent remains in the droplet phase which is trapped in the viscous gel as it forms, it is possible to select an emulsifying agent in which the drug is optimally stable thereby prolonging the stability of the beneficial agent in the gel composition . An additional benefit is the opportunity to schedule release of the beneficial agent by diffusion through the porous structure of the implant rather than by degradation and dissolution of the polymer backbone.

When the beneficial agent is dissolved or dispersed in the emulsifying agent, the injectable depot of the present invention may be provided as an assembly, which comprises as components (a) a mixture of polymer and solvent, (b) emulsifying agent and (c) ) beneficial agent. Prior to use the beneficial agent is mixed with the emulsifying agent and that solution or suspension is mixed with the polymer / solvent mixture to prepare the injectable implant of delayed effect for use. The emulsifying agent is present in an amount ranging from about 5 to about 80%, preferably from about 20 to about 60% and often from 30 to 50% by weight based on the amount of the injectable gel composition of effect that is, the combined amounts of polymer, solvent, emulsifying agent and beneficial agent. Illustrative examples of emulsifying agents are water, alcohols, polyols, esters, carboxylic acids, ketones, aldehydes and mixtures thereof. Preferred emulsifying agents are alcohols, propylene glycol, ethylene glycol, glycerol, water and their solutions and mixtures. Particularly preferred are water, ethanol, and isopropyl alcohol and mixtures thereof. The type of emulsifying agent affects the size of the dispersed droplets. For example, ethanol will provide droplets of average diameters which may be in the order of 10-fold greater than the droplets obtained with an isotonic saline solution containing 0.9% by weight sodium chloride at 21 ° C.

Although no other components are normally present in the composition, where optional conventional ingredients such as polyethylene glycol, hydroscopic agents, stabilizing agents and the like are used, they are used in an amount which does not substantially affect the advantageous results which can be achieved according to with the present invention.

To illustrate still further aspects of the invention, Figure 3 shows the viscosities at different degrees of shear using only water and an aqueous mixture containing 10% by volume of ethanol with a weight ratio of 2: 1 (gel / emulsifying agent) using a viscous gel formed from 50% by weight of a 50:50 lactic acid / glycolic acid copolymer and 50% by weight triacetin compared to the viscosities of the viscous gel without the emulsifying agent.

It will be understood that the emulsifying agent of the present invention is not merely a diluent that reduces viscosity by simply decreasing the concentration of the components of the composition. The use of conventional diluents may reduce the viscosity, but may also cause the above-mentioned blast effect when the diluted composition is injected. In contrast, the injectable delayed effect composition of the present invention may be formulated to avoid the blast effect by selecting the emulsifying agent so that, once injected into the site, the emulsifying agent has little impact on the properties of release from the original system. Other compositions without the beneficial agent may be useful for wound healing, bone treatment and other structural support purposes.

For a better understanding of the various aspects of the present invention, the results presented in the Figures previously described were obtained according to the following examples.

Example 1

Dry spray lysozyme particles of 50% sucrose and 50% chick lysozyme (on a dry weight basis) were obtained.

A viscous gel material was prepared by heating 60% by weight of triacetin with 40% by weight of lactic acid / glycolic acid 50:50 copolymer at 37 ° C overnight. The viscous gel was allowed to cool to room temperature while continuing to mix. The lysozyme particles were added to the viscous gel in a ratio of 20:80 lysozyme: gel (by weight) particles. The blend was blended for five minutes. Immediately prior to use, 90% isotonic saline and 10% ethanol were added to the emulsifying agent. The emulsifying agent contained 1/3 of the total delayed-effect injectable gel composition. 0.5 g of this delayed-effect injectable composition was then injected into a mouse. 23 SGCR-0418

Example 2

A viscous gel material was prepared by heating 60% by weight of triacetin with 40% by weight of a 50:50 lactic acid / glycolic acid copolymer at 37 ° C overnight. The viscous gel was allowed to cool to room temperature while continuing to mix. Immediately prior to use, lysozyme particles, prepared as in Example 1 and in the same amount, are combined with 90% isotonic saline and 10% ethanol as an emulsifying agent in the amount used in Example 1. Mix the emulsifying agent-lysozyme solution with the amount of gel material used in Example 1 to form a delayed-effect injectable gel composition. The produced delayed injectable gel composition is suitable for injection into an animal.

According to several aspects of the present invention one or more significant advantages may be obtained. More specifically, through the use of simple processing steps, a delayed effect gel composition can be obtained which can be injected into a site in an animal without surgery using a low delivery force through standard needles. Once in place, the composition will quickly return to its original viscosity and may exhibit rapid hardening in order to substantially prevent an explosion effect and provide the desired beneficial agent release profile. In addition, once the beneficial agent has been fully administered, there is no need to remove the composition since it is completely biodegradable. Yet as a further advantage, the present invention avoids the use of microparticle or microcapsulating techniques which may degrade certain beneficial agents, such as peptides and nucleic acid-based drugs, and whose microparticles and microcapsules may be difficult to remove from the environment of use. Since the viscous gel is formed without the need for water, extreme temperatures, or other solvents, the suspended particles of the beneficial agent remain dry and in their original configuration, which contributes to their stability. In addition, since a dough is formed, the delayed-effect injectable gel composition can be recovered from the environment of use, if desired.

In all respects respecting the exemplary embodiments of the present invention are intended to be illustrative and not restrictive. Thus, the present invention allows for many variations in a detailed implementation that one skilled in the art can draw from the present disclosure. All such variations and modifications are considered to be within the scope and spirit of the present invention, as defined by the following claims

Lisbon, September 27, 2001

By Applicant

25

Claims (20)

A delayed-effect injectable gel composition comprising: A) a biocompatible polymer; B) a solvent that dissolves the biocompatible polymer and forms a viscous gel; C) an emulsifying agent in the form of a droplet phase dispersed in the viscous gel. The delayed-effect injectable gel composition of claim 1 further comprising a beneficial agent. The delayed-effect injectable gel composition of any one of claims 1 or 2 in which the biocompatible polymer is selected from polylactides, polyglycols, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates , poly (amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, and copolymers, terpolymers and mixtures thereof. The delayed-effect injectable gel composition according to any preceding claim in which the biocompatible polymer is a lactic acid-based polymer. SGCR-0418 The delayed-effect injectable gel composition of claim 4, wherein the lactic acid-based polymer has a ratio of lactic acid to glycolic acid monomers in the range of 100: 0 to about 15:85. The delayed-effect injectable gel composition according to any of claims 4 and 5, wherein the lactic acid-based polymer has an average molecular weight of about 1000 to 120,000. A delayed-effect injectable gel composition according to any preceding claim, wherein the solvent which can dissolve the biocompatible polymer to form a viscous gel is selected from triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid, and 1-dodecylazacycloheptan-2-one and mixtures thereof. The delayed-effect injectable gel composition according to any preceding claim in which the polymer is present in an amount of about 5 to 80% by weight of the combined amounts of the polymer and the solvent. A delayed-effect injectable gel composition according to any preceding claim, wherein the solvent is present in an amount of substantially 95 to 20% by weight of the combined amounts of the polymer and the solvent. 2 SGCR-0418 \ The delayed-effect injectable gel composition according to any preceding claim, wherein the viscous gel formed by the polymer and the solvent has a viscosity of about 1000 to 200,000 poise. The delayed-effect injectable gel composition of any one of claims 2 to 10, wherein the beneficial agent is selected from a drug, peptide, protein, or growth hormone. The delayed-effect injectable gel composition of any one of claims 2 to 11, wherein the beneficial agent is present in an amount of about 1 to 50% by weight of the combined amounts of the polymer, the solvent and the beneficial agent. A delayed-effect injectable gel composition according to any of claims 2 to 12, in which the beneficial agent is in the form of particles dispersed or dissolved in the viscous gel. The delayed-effect injectable gel composition of claim 13, wherein the beneficial agent is in the form of particles having an average particle size of from about 0.1 to 100 microns. A delayed-effect injectable gel composition according to any preceding claim, wherein the emulsifying agent is SGCR-0418 selected from water, alcohols, polyols, esters, carboxylic acids, ketones, aldehydes, and mixtures thereof. A delayed-effect injectable gel composition according to any preceding claim, in which the emulsifying agent is selected from alcohols, propylene glycol, ethylene glycol, glycerol, water and their solutions and mixtures. A delayed-effect injectable gel composition according to any preceding claim, wherein the emulsifying agent is selected from ethanol, isopropyl alcohol, water, its solutions and mixtures. A delayed-effect injectable gel composition according to any preceding claim, wherein the emulsifying agent is present in an amount of about 5 to 80% by weight of the delayed-effect injectable gel composition. A process for the preparation of an injectable gel composition having a delayed effect, comprising the steps of: (A) mixing a biocompatible polymer and a solvent, which dissolves the polymer and forms a viscous gel; B) dispersing or dissolving a beneficial agent in the viscous gel to form a beneficial agent containing a viscous gel; and C) mixing an emulsifying agent with the beneficial agent containing a viscous gel wherein said emulsifying agent forms a dispersed droplet phase SGCR-0418 in the beneficial agent containing a viscous gel to provide the injectable gel composition having a delayed effect. A process for the preparation of an injectable gel composition having a delayed effect, comprising the steps of: (A) mixing a biocompatible polymer and a solvent, which dissolves the polymer to form a viscous gel; B) dispersing or dissolving a beneficial agent in an emulsifying agent to form a beneficial agent containing emulsifying agent; and C) mixing the beneficial agent containing the emulsifying agent with the viscous gel; wherein said beneficial agent containing emulsifying agent forms a droplet phase dispersed in the viscous gel to provide the injectable composition having a delayed effect. Lisbon, September 27, 2001 By the Applicant 5